Schut et al. (U.S. Pat. No. 4,283,410[Aug. 11, 1981]; U.S. Pat. No. 4,283,336[Aug. 11, 1981]) and Safdy et al. (J. Medic. Chem. 25[6], 724 [1982]) have synthesized 3-amino-2-(5-methoxy-1H-indol-3-yl)propionic acid characterized by the structural formula: ##STR3## The authors state that the compound is therapeutically useful as an anti-hypertensive agent.
The synthesis of 3-amino-2-(5-methoxy-1H-indol-3-yl)propionic acid, reported in the two above cited patents and in the above cited publication, is a laborious and expensive sequence of reactions starting with 5-methoxyindole-3-acetonitrile characterized by the structural formula: ##STR4## which is reated with an alkali metal base and acyloxylating agent to produce ethyl 2-cyano-2-(1-ethoxycarbonyl-5-methoxy-1H-indol-3-yl)acetate characterized by the structural formula: ##STR5## which is hydrogenated under pressure in the presence of a ctalyst in a solvent also acting as an acylating agent to provide ethyl 3-acetylamino-2-(1-ethoxycarbonyl-5-methoxy-1H-indol-3-yl)propanoate characterized by the structural formula: ##STR6## The above compound is hydrolyzed with an aqueous solution of an alkali metal hydroxide to produce a compound characterized by the formula: ##STR7## and then decarboxylated to produce the desired 3-amino-2-(5-methoxy-1H-indol-3-yl)propionic acid, whose structural formula is given above.
In turn, the authors prepared 5-methoxyindole-3-acetonitrile as JUBY and HUDYMA, J. Med. Chem. 12[2], 396[1969] from 5-methoxyindole under the reaction conditons reported by WALTON et al; J. Med. Chem. [2], 204[1965]. This requires the conversion of 5-methoxyindole into 3-formyl-5-methoxyindole, which is then transformed into 5-methoxygramine characterized by the formula: ##STR8## Treatment of 5-methoxygramine with methyl iodide gave the quaternary ammonium salt which after reaction with cyanide ion provided the desired 5-methoxyindole-3-acetonitrile whose structural formula is given above.
Looking further back for the synthesis of the required 5-methoxyindole, it becomes clear that para-methoxyphenylhydrazine can be reacted in an acid solution with pyruvic acid and the in situ formed para-methoxyphenylhydrazone converted into indole-2-carboxylic acid, which is then decarboxylated to afford 5-methoxyindole.
Later, Schut et al. (U.S. Pat. No. 4,393,081[Jul. 12, 1983]) also have synthesized methyl 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propanoate characterized by the structural formula: ##STR9## The authors state that the compound is also therapeutically useful as an anti-hypertensive agent.
The preparation of methyl 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propanoate, reported in U.S. Pat. No. 4,393,081, is done by either of two methods.
The first of these methods uses methyl 3-amino-2-(5-methoxy-1H-indol-3-yl)propanoate hydrochloride characterized by the structural formula: ##STR10## which is reacted with an acylating agent in the presence of an amine to provide methyl 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propanoate, whose structural formula is given above.
In turn, in U.S. Pat. No. 4,283,336 and in U.S. Pat. No. 4,283,410, the authors describe the preparation of methyl 3-amino-2-(5-methoxy-1H-indol-3-yl)propanoate hydrochloride, whose structural formula is given above, by treatment of 3-amino-2-(5-methoxy-1H-indol-3-yl)propionic acid, whose structural formula is given above, with an alcohol in the presence of an acid catalyst, followed by conversion of the reaction product into a salt by treatment with a mineral acid.
The second of these methods for the preparation of methyl 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propanoate uses 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propionic acid, characterized by the structural formula: ##STR11## which is reacted with an alcohol in the presence of an acid catalyst to provide methyl 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propanoate, whose structural formula is given above.
In turn, in U.S. Pat. No. 4,283,336 and in U.S. Pat. No. 4,283,410, the authors describe the preparation of 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propionic acid, whose structural formula is given above, by treatment of ethyl 3-acetylamino-2-(1-ethoxycarbonyl-5-methoxy-1H-indol-3-yl)propanoate, whose structural formula is given above, with an aqueous solution of an alkali metal hydroxide, followed by neutralization of the solution with a mineral acid.
Thus, many reaction conditions have to be performed to convert para-methoxyphenyldrazine characterized by the structural formula: ##STR12## into the therapeutically useful compound 3-amino-2-(5-methoxy-1H-indol-3-yl)propionic acid having the structural formula given above, or into the therapeutically useful compound methyl 3-acetylamino-2-(5-methoxy-1H-indol-3-yl)propanoate having the structural formula given above.